The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerve bundle, and more particularly to techniques for treating patients with dementia by application of such signals to the patient's vagus nerve with a neurostimulating device.
Dementia is generally defined as deterioration or loss of intellectual faculties, reasoning power, memory and will due to organic brain disease; characterized by confusion, disorientation, apathy and stupor of varying degrees. It is important to note that although memory and level of alertness may be affected, these are separate processes. Therapies such as stimulants may affect alertness, yet have no effect on intellectual faculties, and therefore are not effective in the treatment of dementia.
Various causes of dementia have been described in the scientific literature, but approximately one-half of all dementia cases are thought to be attributable to Alzheimer's disease. Other common causes of forms of the disorder include numerous small strokes (leading to multi-infarct dementia), and cerebrovascular disease.
The literature also describes the occurrence of electroencephalogram (EEG) changes in patients with dementia. Although results of studies vary somewhat, several findings appear to be fairly consistent. The most common observation seems to be that dementia, especially in patients with Alzheimer's disease, is associated with slowing of the EEG rhythm. Paroxysmal activity is seen less consistently, but in up to half the patients in some series. A review of some relatively recent papers is informative.
Hughes et al. reported in Clin. Electroencephalog. (1989) 20(2):77-85, on a study of eighty-three patients with dementia. All were found to have excessive slow wave activity, and the degree of diffuse slowing was correlated with the degree of dementia. Sharp waves, emanating primarily from the temporal lobes, were found to be present in 23 percent of the patients.
In J. Clin. Psychol. (1989) 45(1):117-123, Kurlychek observed that in patients with senile dementia of the Alzheimer's type (SDAT), the normal alpha rhythm is usually reduced, and diffuse slower theta and delta waves are more prominent. In multi-infarct dementia, the background alpha rhythm tends to be more preserved, and slowing tends to be more focal rather than diffuse as with SDAT. The EEG tends to be in the normal range in other forms of dementia, such as normal pressure hydrocephalus and Pick's disease.
Ettlin et al., in Arch. Neurol. (1989) 46:1217-1220, reported that diagnostic EEG criteria for dementia included overall disturbance (slowing of the dominant rhythm, with appearance of diffuse theta and delta waves), asymmetric findings (localized slow wave activity, paroxysmal activity), and bifrontal burst of delta waves.
Verma et al., in Clin. Electroencephalog. (1987) 18(1):26-33, reported finding that 14 out of 15 patients with cortical dementia (such as Alzheimer's and Pick's) had abnormal EEGs. In contrast, the EEG of 14 out of 15 patients with subcortical dementia (associated with conditions such as supranuclear palsy, Huntington's chorea, and Parkinson's disease) tended to be normal. The degree of abnormality tended to correlate with the degree of dementia. Abnormalities consisted primarily of slowing of the background rhythm and excess theta and delta wave activity. Paroxysmal activity was not seen in this series.
An Acta Nerol. Scand. (1988) 77:36-43 paper by Erkinjunti et al. reported finding that in patients with Alzheimer's disease, the degree of EEG abnormality correlated to the degree of dementia. Such correlation was not observed in patients with multi-infarct and probable vascular dementia. Focal abnormalities were seen in 18 percent of the Alzheimer's patients. Paroxysmal activity was observed in about 45 percent of patients with Alzheimer's disease, and in even greater numbers with the other types of dementia. The occurrence of paroxysmal activity was not related to the degree of dementia.
Thus far, techniques for treating and/or controlling dementia have had little success. In the main, the treatment of choice has been the use of drugs of various types, including stimulants.
The present invention is directed to methods and devices for treating and controlling dementia by selective stimulation of the vagus nerve (the tenth cranial nerve) in a predetermined manner according to the EEG abnormalities associated with the particular case of the dementia. Several mechanisms are potentially involved. If paroxysmal activity is present, vagal stimulation may serve to suppress this activity. Although paroxysmal activity has not been observed in the majority of cases reported in the papers cited above, it may be present in deeper structures in all dementia patients. Another mechanism by which vagal stimulation can be beneficial in treating dementia is its effect on the reticular formation or activating system, the network of neurons involved in controlling the level of alertness. Stimulation of this system may directly affect alertness and cognitive functions by arousal of higher brain centers.
The neural processes involved in memory are complex, but it is known that hippocampal structures are involved in memory processing. It is postulated further that vagal stimulation can affect hippocampal activity in a way to prevent or inhibit deterioration of memory.
With reference to FIG. 1, simplified representations of the EEGs of persons exhibiting normal activity, excessive slow wave activity, and paroxysmal activity are shown in parts (a), (b) and (c), respectively. In essence, an EEG is a picture of the integration of activity from millions of brain cells, and, in an awake, alert individual, should have the appearance of a noise pattern because the cells are operating independently. Rhythmic alpha activity emanating from the occipital region is normal in such subjects. However, when the brain is driven by a synchronizing force, it may slow the EEG down and produce higher voltage, or cause high voltage synchronous spikes, or spikes and slow waves. In general, the normal person's EEG displays low voltage and relatively fast activity (FIG. 1(a)). Situations do occur in which the EEG activity slows down, such as during sleep, and displays higher voltage, but this is normal. In contrast, individuals with dementia, brain tumors and certain other disorders exhibit slow wave activity and higher voltage in an abnormal EEG (FIG. 1(b)). Paroxysmal activity is somewhat similar to the latter, but with somewhat faster wave activity and higher synchronous spikes (FIG. 1(c )). Both of the EEGs of FIGS. 1(b) and (c) are more synchronized than the normal EEG of FIG. 1(a), although that synchrony exists in different ways, e.g., the paroxysmal EEG is more synchronized with faster activity and larger signals.
In studying the intellectual function (I.F.) of individuals versus age, it is observed that the intellectual function of a person with Alzheimer's disease declines much more rapidly than does the intellectual function of the general population with advancing years. A simple plot of I.F. versus age is shown in FIG. 2. Age alone is not indicative of the disease. Advanced age is not invariably associated with loss of function, and it may be argued that all loss of function is related to some abnormal process. An important object of the present invention is to provide a therapy utilizing vagal stimulation which may be instituted at some point on the declining curve 1, representative of a person suffering from Alzheimer's disease or other form of progressive dementia, so as to at least slow down the process and even possibly to arrest the decline. This is indicated by curve 2 which is parallel to or declining at only a moderately faster rate than the normal decline of curve 3 found in the general population. It is unlikely, however, that the patient would experience any reversal of the process. From an efficacy standpoint, the patient population to be treated or likely to experience the most favorable results are those individuals at a moderate stage rather than the more advanced stages of the disease.
Certain anatomical changes that occur with Alzheimer's disease are detectable only during autopsy or brain biopsy, making early diagnosis difficult. Recent findings, however, indicate that neurologic and mental status can be used to diagnose the disease in its early stages. It is somewhat more difficult to correctly diagnose the early stages of certain other types of dementia, such as multi-infarct dementia.
It is known that most nerves in the human body are composed of thousands of fibers, of different sizes designated by groups A, B and C, which carry signals to and from the brain. The vagus nerve, for example, may have approximately 100,000 fibers of the three different types, each carrying signals. Each axon (fiber) of that nerve only conducts in one direction, in normal circumstances. The A and B fibers are myelinated (i.e., have a myelin sheath, constituting a substance largely composed of fat), whereas the C fibers are unmyelinated.
Myelinated fibers are typically larger, conduct faster and have very low stimulation thresholds, compared to the unmyelinated type. Very little energy is required to stimulate the myelinated fibers, and they exhibit a particular strength-duration curve or respond to a specific pulse width versus amplitude for stimulation. The A and B fibers can be stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. The A fiber conducts slightly faster than the B fiber and has a slightly lower threshold. The C fibers are very small, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring a wider pulse width (300-1000 .mu.s) and a higher amplitude for activation. Selective stimulation of only A and B fibers is readily accomplished. The requirement of a larger and wider pulse to stimulate the C fibers, however, makes selective stimulation of only C fibers, to the exclusion of the A and B fibers, virtually unachievable inasmuch as the large signal will tend to activate the A and B fibers to some extent as well.
Usually, nerve stimulation activates signals in both directions (bidirectionally). It is possible, however, through the use of special electrodes and waveforms, to selectively stimulate a nerve in one direction only (unidirectionally).
In a paper on the effects of vagal stimulation on experimentally induced seizures in rats (Epilepsia 1990, 31 (Supp 2): S7-S19), Woodbury notes that the vagus nerve is composed of somatic and visceral afferents (inward conducting nerve fibers that convey impulses toward a nerve center such as the brain or spinal cord) and efferents (outward conducting nerve fibers that convey impulses to an effector to stimulate same and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the neck. The central projections terminate, by and large, in the nucleus of the solitary tract which sends fibers to various regions of the brain (e.g, the hypothalamus, thalamus, and amygdala); others continue to the medial reticular formation of the medulla, the cerebellum, the nucleus cuneatus and other regions.
Woodbury further notes that stimulation of vagal nerve afferent fibers in animals evokes detectable changes of the EEG in all of these regions, and that the nature and extent of these EEG changes depends on the stimulation parameters. Chase, in Exp Neurol (1966) 16:36-49, had also observed that vagal activation can affect the EEG activity of certain parts of the brain. The applicants herein postulate that synchronization of the EEG may be produced when high frequency (&gt;70 Hz) weak stimuli activate only the myelinated (A and B) nerve fibers, and that desynchronization of the EEG occurs when intensity of the stimulus is increased to a level that activates the unmyelinated (C) nerve fibers. Woodbury also observes that vagal stimulation can produce widespread inhibitory effects on seizures and certain involuntary movements.
Extra-physiologic electrical stimulation of the vagus nerve has previously been proposed for treatment of epilepsy and various forms of involuntary movement disorders. Specifically, in U.S. Pat. No. 4,702,254 issued Oct. 27, 1987 to J. Zabara (referred to herein as "the '254 patent"), a method and implantable device are disclosed for alleviating or preventing epileptic seizures, characterized by abnormal neural discharge patterns of the brain. The '254 patent describes an implantable neurocybernetic prosthesis (NCP) which utilizes neurocybernetic spectral discrimination by tuning the external current of the NCP generator to the electrochemical properties of a specific group of inhibitory nerves that affect the reticular system of the brain. These nerves are embedded within a bundle of other nerves, and are selectively activated directly or indirectly by the tuning of the NCP to augment states of brain neural discharge to control convulsions or seizures. According to the patent, the spectral discrimination analysis dictates that certain electrical parameters of the NCP pulse generator be selected based on the electrochemical properties of the nerves desired to be activated. The patent further indicates that the optimum sites for application of the NCP generator output to produce the desired effects are the cranial nerves in general, and the vagus nerve in particular.
The NCP disclosed in the '254 patent may be activated either manually or automatically, to provide treatment for the duration of the seizure. Manual activation is performed when the patient experiences the aura at onset of the seizure. Alternatively, automatic activation may be triggered upon detection of instantaneous changes in certain state parameters immediately preceding or at onset of a seizure. Additionally, a prophylactic or preventive mode may be employed in which the NCP is activated periodically to reduce the occurrence and/or the intensity of the seizures. The NCP stimulator of the '254 patent is implanted in the patient's chest and is connected to electrodes installed at the selected point of signal application at the nerve site with the more negative electrode situated closer to the brain and the positive electrode further from the brain, along the vagus nerve.
The '254 patent mentions Parkinson's disease in conjunction with the category of involuntary movement disorders which may be treated with vagal stimulation. The present invention in one of its aspects is directed toward the treatment and control of subcortical dementia, which as a matter of interest encompasses conditions such as Parkinson's disease, Huntington's chorea, and supranuclear palsy. It is noteworthy that the latter forms of dementia involve motor functions that are different from the spasticity or involuntary movement disorders mentioned and proposed for treatment by the methods and apparatus of the '254 patent. For example, Parkinson's disease has several manifestations, one of which is tremor--involuntary movement. But another even more prominent manifestation is the tendency of the patient to react and move very slowly (referred to as bradykinesia)--a reduced amount of voluntary movement. In contrast, then, to involuntary movement disorders addressed in the '254 patent, the aspect of the present invention which is directed toward treatment of subcortical dementia deals in part with brain functions that inhibit or decrease voluntary movement and control. That is, a principal aspect of treatment of dementia according to the invention involves control of the cognitive functions--mental processes of comprehension and reasoning,--but a subordinate aspect involves potential control of voluntary movement functions associated with some types of dementia. In part, the latter is driven by brain stem centers that may be affected by the reticular formation which, in turn, is affected by vagal stimulation.